[Neurological phenocopying]

Abstract

Aims: To expand the -supposedly- narrow relationships that exist between genes and clinical syndromes by reflecting on several illustrative examples that disturb current simplistic genotype: phenotype correlations, and to explore a variety of biological mechanisms that account for this emerging phenomenon.

Development: Because it is well known that mutations in a single gene can give rise to numerous phenotypes, it would appear, at least intuitively, that the converse relationship might also hold true: that different genotypes may converge on just one single phenotype. Several examples taken from the study of selected neurological diseases illustrate that the latter principle indeed occurs in nature because disparate human genetic anomalies manifest similarly by exhibiting only a relatively limited phenotypic repertoire. This interesting biological phenomenon and vexing clinical problem is best described as phenocopying. Conditions such as spinal muscular atrophy, congenital glycosylation disorders, and mitochondrial diseases are but a few notorious examples of phenocopying.

Conclusion: The nervous system is endowed with a limited number of genes and of types of molecules and, especially during development, its functional repertoire, at least from an observable point of view, is also limited. Therefore, ample genotyping capabilities are necessary to avoid erring in the process of diagnostic attribution because of phenocopying.